Compounds

ABSTRACT

A compound having the general formula  
                 
and methods of using such compounds for the treatment of diseases and pharmaceutical composition comprising such compounds.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/381,755 filedMar. 26, 2003, which is the National Stage of PCT Application No.PCT/SE01/02100, filed Sep. 27, 2001, which claims the benefit under 35U.S.C. § 119(a-d) of Application No. 0003476-9 filed in Sweden on Sep.28, 2000.

BACKGROUND

The mammalian neurokinins comprise a class of peptide neurotransmitterswhich are found in the peripheral and central nervous systems. The threeprincipal neurokinins are Substance P (SP), Neurokinin A (NKA) andNeurokinin B (NKB).

There are also N-terminally extended forms of at least NKA. At leastthree receptor types are known for the three principal neurokinins.Based upon their relative selectivities favoring the neurokinin agonistsSP, NKA and NKB, the receptors are classified as neurokinin 1 (NK₁),neurokinin 2 (NK₂) and neurokinin 3 (NK₃) receptors, respectively.

It is now recognized that anxiety, stress, and depression areinterrelated conditions (File SE Pharmacol, Biochem & Behavior54/1:3-12, 1996). Moreover, these complex emotional states cannot be duesimply to defects in a single neurotransmitter although 5-HT has beenascribed a principal role (Graeff et al., Pharmacol, Biochem & Behavior54/1: 129-141, 1996). Substance P (SP) was one of the firstneuropeptides to be identified in mammalian brain and it is now acceptedthat all three tachykinins are found within the CNS (Iversen L L JPsychopharmacol 3/1:1-6, 1989), particularly in the striatonigralneurons, hypothalamus and limbic forebrain (ibid). NK₁ and NK₃ receptorshave been identified in the brain as well (Beaujouan et al., Neurosci.18: 857-875, 1986). Controversy has existed regarding the presence ofthe NK₂ receptor in brain, although recent evidence shows receptorlocalization in at least the septal region (Steinberg et al., Eur JNeurosci 10/7:2337-45 1998).

Pharmacological evidence supporting a role for either NK₁ or NK₂receptors in anxiety disorders has been accumulating from assortedanimal behavioral tests (for examples, see Table 1). Animal models ofdepression, however, have been used rarely to define the potentialutility of NK receptor antagonists. SP stimulates the turnover of otherneurotransmitters involved in depression, i.e., 5-HT in the raphenucleus, an area thought to be linked to depressive phenomena (Forchettiet al., J. Neurochem. 38: 1336-1341, 1982). When injected centrally tonuclei responsible for control of emotion and stress, SP evokes ahemodynamic pressor response bridging this peptide to stress inducedhypertension (Ku et al., Peptides; 19/4:677-82, 1998). Moreover, risesin both heart rate and mean arterial blood pressure evoked by physicalstress can be blocked in rodents by centrally administered NK₁ receptorantagonists (Culman et al., J Pharmacol Exp Ther 280/1:238-46, 1997).TABLE 1 Neurokinin receptor antagonist activity in behavioral tests ofanxiety/depression. Cpd (Receptor Author type) Behavioral Test OutcomeTeixeira et al., NK₁ agonists & Elevated plus-maze agonists - Eur JPharmacol FK888 (NK₁) anxiogenic 5; 311(1): 7-14, 1996. SR48968 (NK₂)antagonists - anxiolytic File Pharm Bio B CGP 49823 Social interactionanxiolytic 58(3): 747-752, 1997. (NK₁) Vassout et al CGP 49823 Socialinteraction test anxiolytic Neuropeptides (NK₁) Elevated plus-mazeinactive 26/S1: 38, 1994. Forced swim test antidepressant (depressionmodel) (only at 30 mg/kg bid) Stratton et al., Eur. GR100679 Light-darkbox anxiolytic J. Pharmacol. 250: (NK₂) R11-12, 1993. SR48968 (NK₂)Walsh et al., GR159897 Light-dark box anxiolytic Psychopharmacology(NK₂) Marmoset human anxiolytic 121: 186-191, 1995. SR48968 (NK₂)intruderDescription

This invention relates to internally cyclized benzamide compounds; topharmaceutical compositions containing such compounds; as well as totheir uses and processes for their preparation. These compoundsantagonize the pharmacological actions of the neurokinin 1 (NK₁)receptor. These compounds are useful whenever such antagonism isdesired. Thus, such compounds are of value in the treatment of thosediseases in which Substance P is implicated, for example, in thetreatment of major depressive disorder, severe anxiety disorders, stressdisorders, major depressive disorder with anxiety, eating disorders,bipolar disorder, substance use disorder, schizophrenic disorders,psychotic disorders, movement disorders, cognitive disorders, depressionand/or anxiety, mania or hypomania, aggressive behaviour, obesity,emesis, rheumatoid arthritis, Alzheimer's disease, cancer, oedema,allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility,Huntington's disease, chronic obstructive pulmonary disorder (COPD),hypertension, migraine, bladder hypermotility, or urticaria.

Accordingly, the present invention provides the compounds of the generalformula Ia:

The compounds of the present invention may possess a number of chiralcentres, for example at —CH(Ph-X¹,X²)—, and at —CH(R²)—. The presentinvention covers all isomers, diastereoisomers and mixtures thereof thatantagonize NK₁.

The preferred configuration at —CH(Ph-X¹,X²)— is shown in formula (Ib)hereinbelow:

X¹ and X² are independently hydrogen or halo, provided that at least oneof X¹ or X² is halo. Favourably, X¹ and X² are both chloro. In apreferred aspect Ph-X¹,X² is 3,4-dichlorophenyl.

R^(1a) is H, NR⁹R¹⁰, —OR⁹,

R^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) and R^(1c)together are ═O, ═CH₂ or —OCH₂CH₂O—.

In one embodiment, R^(1a) is H, NR⁹R¹⁰ or —OR⁹. In another embodiment,R^(1a) is

R^(1b) is H and R^(1c) is H. And in another embodiment, R^(1a) is

R^(1b) is H and R^(1c) is H.

R² is H, oxo, —OR⁹ or —CH₃. In one embodiment, R² is —OR⁵ or —CH₃.

The naphthyl group of Ia is an optionally substituted naphth-1-yl.Suitable substituents, which are optional, for the naphth-1-yl groupinclude hydroxy; cyano; nitro; trifluoromethoxy; trifluoromethyl;C₁₋₆alkylsulfonyl for example methylsulphonyl; halo for example chloro,bromo, fluoro or iodo; C₁₋₆alkoxy for example methoxy, ethoxy orpropoxy; methylenedioxy (—OCH₂O—), C₁₋₆alkyl for example methyl orethyl; C₂₋₆alkenyl for example ethenyl, prop-1-enyl or prop-2-enyl;C₂₋₆alkynyl for example ethynyl; carboxy, C₁₋₆alkoxy-carbonyl forexample methoxycarbonyl; carbamoyl; C₁₋₆alkylcarbamoyl for examplemethylcarbamoyl or ethylcarbamoyl; di-C₁₋₆alkylcarbamoyl for exampledi-methylcarbamoyl; C₁₋₆alkanoyl for example acetyl or propionyl;C₁₋₆alkanoylamino for example acetylamino or propionylamino;aminosulfonyl; and C₁₋₆alkyl for example methyl substituted by any ofthe hereinabove substituents.

Favourably the naphth-1-yl group is unsubstituted or is substituted byup to three substituents. Preferred substituents for the naphth-1-ylgroup include cyano; nitro; C₁₋₆alkylsulfonyl for examplemethylsulphonyl; halo for example chloro, bromo, fluoro or iodo;C₁₋₆alkoxy for example methoxy, ethoxy, n-propoxy or isopropoxy;methylenedioxy (—OCH₂O—); C₁₋₆alkyl for example methyl or ethyl;C₂₋₆alkenyl for example prop-2-enyl; C₂₋₆alkynyl for example ethynyl;carboxy, carbamoyl; C₁₋₆alkyl-carbamoyl for example methylcarbamoyl;di-C₁₋₆alkylcarbamoyl for example di-methylcarbamoyl; C₁₋₆alkanoyl forexample acetyl; C₁₋₆alkanoylamino for example acetylamino;aminosulfonyl; and cyanoC₁₋₆alkyl for example cyanomethyl.

More preferred substitutents for the naphth-1-yl group are cyano,methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro,cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl,dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyland acetylamino.

In particular the naphth-1-yl group may be substituted by up to threesubstituents selected from cyano, methoxy, ethyl, fluoro and nitro.

R³, R⁴, R⁵ and R⁶ are each independently selected from H, cyano, nitro,trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and C₁₋₆alkyl substituted by anyof the hereinabove substituents; wherein at least one of R³, R⁴, R⁵ andR⁶ are H.

In one embodiment, R³, R⁴, R⁵ and R⁶ are selected from H, cyano, nitro,—S(═O)C₁₋₆alkyl, halo, —OR⁹, —OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —NR⁹C(═O)R¹⁰,aminosulfonyl and —C₁₋₆alkylcyano; wherein at least two of R³, R⁴, R⁵and R⁶ are H.

In another embodiment, R³, R⁴, R⁵ and R⁶ are selected from H, cyano,methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro,cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl,dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyland acetylamino; wherein at least three of R³, R⁴, R⁵ and R⁶ are H.

In another embodiment, R³, R⁴, R⁵ and R⁶ are selected from H, cyano,methoxy, ethyl, fluoro and nitro; wherein at least two of R³, R⁴, R⁵ andR⁶ are H.

R⁹ and R¹⁰ are each independently H or C₁₋₆alkyl;

R¹¹ is phenyl, substituted in at least the ortho position byC₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,trifluoromethylthio, trifluoromethylsulfinyl, C₁₋₆alkanesulfonamido,C₁₋₆alkanoyl, C₁₋₆alkoxy-carbonyl, succinamido, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,C₁₋₆alkoxy-C₁₋₆alkylcarbamoyl, N-methylcarbamoyl, C₁₋₆alkanoylamino,ureido, C₁₋₆ureido, di-C₁₋₆alkylureido, amino, C₁₋₆alkylamino, ordi-C₁₋₆alkylamino.

R¹² is selected from hydrogen, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy,C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆anoylamino, C₁₋₆alkyl, carbamoyl,C₁₋₆alkylcarbamoyl and bis(C₁₋₆alkyl)carbamoyl.

R¹³ is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—.

R¹⁴ is hydrogen, hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy, C₁₋₆alkanoyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino, C₁₋₆alkyl, carbamoyl,C₁₋₆alkylcarbamoyl or di-C₁₋₆alkylcarbamoyl.

M is —C(═O)— or —S(═O)₂—.

L is —NH— or —CH₂—.

Y and Z are CH₂ or O, wherein Y does not equal Z.

n is 0 or 1.

Another aspect of the invention involves a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formulaIa.

Another aspect of the invention involves a method of treating majordepressive disorder, severe anxiety disorders, stress disorders, majordepressive disorder with anxiety, eating disorders, bipolar disorder,substance use disorder, schizophrenic disorders, psychotic disorders,movement disorders, cognitive disorders, depression and/or anxiety,mania or hypomania, aggressive behaviour, obesity, emesis, rheumatoidarthritis, Alzheimer's disease, cancer, oedema, allergic rhinitis,inflammation, pain, gastrointestinal-hypermotility, Huntington'sdisease, COPD, hypertension, migraine, bladder hypermotility, orurticaria comprising administering an effective amount of an NK1antagonist of formula Ia.

Particular compounds of this invention are provided as the Exampleshereinbelow.

C_(Y-Z)alkyl, unless otherwise specified, means an alkyl chaincontaining a minimum Y total carbon atoms and a maximum Z total carbonatoms. These alkyl chains may be branched or unbranched, cyclic, acyclicor a combination of cyclic and acyclic. For example, the followingsubstituents would be included in the general description “C₄₋₇alkyl”:

Pharmaceutically-acceptable salts may be prepared from the correspondingacid in conventional manner. Non-pharmaceutically-acceptable salts maybe useful as intermediates and as such are another aspect of the presentinvention.

The symbol “═O” means a double bonded oxygen, and when this symbol isused attached to a carbon it forms a carbonyl group.

Some of the compounds of the present invention are capable of formingsalts with various inorganic and organic acids and bases and such saltsare also within the scope of this invention. Examples of such acidaddition salts include acetate, adipate, ascorbate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate,glycolate, hemisulfate, 2-hydroxyethyl-sulfonate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate,malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate,oxalate, pamoate, persulfate, phenylacetate, phosphate, picrate,pivalate, propionate, quinate, salicylate, stearate, succinate,sulfamate, sulfanilate, sulfate, tartrate, tosylate(p-toluenesulfonate), and undecanoate. Base salts include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as aluminum, calcium and magnesiumsalts, salts with organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, ornithine, and so forth. Also, basic nitrogen-containing groupsmay be quaternized with such agents as: lower alkyl halides, such asmethyl, ethyl, propyl, and butyl halides; dialkyl sulfates likedimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such asdecyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzylbromide and others. Non-toxic physiologically-acceptable salts arepreferred, although other salts are also useful, such as in isolating orpurifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

In order to use a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically acceptable salt and pharmaceutically acceptablecarrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, topical, parenteral, buccal, nasal, vaginal orrectal administration or by inhalation or insufflation. For thesepurposes the compounds of this invention may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions, suspensions, emulsions, creams, ointments,gels, nasal sprays, suppositories, finely divided powders or aerosols ornebulisers for inhalation, and for parenteral use (includingintravenous, intramuscular or infusion) sterile aqueous or oilysolutions or suspensions or sterile emulsions.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain, or be co-administered(simultaneously or sequentially) with, one or more pharmacologicalagents of value in treating one or more disease conditions referred toherein.

The pharmaceutical compositions of this invention will normally beadministered to humans so that, for example, a daily dose of 0.01 to 25mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) isreceived. This daily dose may be given in divided doses as necessary,the precise amount of the compound received and the route ofadministration depending on the weight, age and sex of the patient beingtreated and on the particular disease condition being treated accordingto principles known in the art.

Typically unit dosage forms will contain about 1 mg to 500 mg of acompound of this invention. For example a tablet or capsule for oraladministration may conveniently contain up to 250 mg (and typically 5 to100 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof. In another example, for administration byinhalation, a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof may be administered in a daily dosage range of 5to 100 mg, in a single dose or divided into two to four daily doses. Ina further example, for administration by intravenous or intramuscularinjection or infusion, a sterile solution or suspension containing up to10% w/w (and typically 5% w/w) of a compound of the formula (I) or apharmaceutically acceptable salt thereof may be used.

Therefore in a further aspect, the present invention provides a compoundof the formula (I) or a pharmaceutically acceptable salt thereof for usein a method of therapeutic treatment of the human or animal body.

In yet a further aspect the present invention provides a method oftreating a disease condition wherein antagonism of the NK₁ receptor isbeneficial which comprises administering to a warm-blooded animal aneffective amount of a compound of the formula (I) or apharmaceutically-acceptable salt thereof. The present invention alsoprovides the use of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof in the preparation of a medicament for use in adisease condition wherein antagonism of the NK₁ receptor is beneficial.

The compounds of the formula (I) and their pharmaceutically acceptablesalts may be made by processes as described and exemplified herein andby processes similar thereto and by processes known in the chemical art.If not commercially available, starting materials for these processesmay be made by procedures which are selected from the chemical art usingtechniques which are similar or analogous to the synthesis of knowncompounds.

It is well known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form or by synthesis fromoptically-active starting materials) and how to determine the NK₁antagonist properties by the standard tests known in the art and thosedescribed hereinafter.

Some individual compounds within the scope of this invention may containdouble bonds. Representations of double bonds in this invention aremeant to include both the E and the Z isomer of the double bond.Additionally, some species within the scope of this invention maycontain one or more asymmetric centers. This invention includes the useof any of the optically pure stereoisomers as well as any combination ofstereoisomers.

The following biological test methods, data and Examples serve toillustrate and further describe the invention.

The utility of a compound of the invention or a pharmaceuticallyacceptable salt thereof (hereinafter, collectively referred to as a“compound”) may be demonstrated by standard tests and clinical studies,including those disclosed in the publications described below.

SP Receptor Binding Assay (Test A)

The ability of a compound of the invention to antagonize the binding ofSP at the NK₁ receptor may be demonstrated using an assay using thehuman NK₁ receptor expressed in Mouse Erythroleukemia (MEL) cells. Thehuman NK₁ receptor was isolated and characterized as described in: B.Hopkins, et al. “Isolation and characterization of the human lung NK₁receptor cDNA” Biochem. Biophys. Res. Comm., 1991, 180, 1110-1117; andthe NK₁ receptor was expressed in Mouse Erythroleukemia (MEL) cellsusing a procedure similar to that described in Test B below.

Neurokinin A (NKA) Receptor Binding Assay (Test B)

The ability of a compound of the invention to antagonize the binding ofNKA at the NK₂ receptor may be demonstrated using an assay using thehuman NK₂ receptor expressed in Mouse Erythroleukemia (MEL) cells, asdescribed in: Aharony, D., et al. “Isolation and PharmacologicalCharacterization of a Hampster Neurokinin A Receptor cDNA” MolecularPharmacology, 1994, 45, 9-19.

The selectivity of a compound for binding at the NK₁ and the NK₂receptors may be shown by determining its binding at other receptorsusing standard assays, for example, one using a tritiated derivative ofNKB in a tissue preparation selective for NK₃ receptors. In general, thecompounds of the invention which were tested demonstrated statisticallysignificant binding activity in Test A and Test B with a K_(i) of 1 mMor much less typically being measured.

Rabbit Pulmonary Artery: NK₁ In Vitro Functional Assay (Test C)

The ability of a compound of the invention to antagonize the action ofthe agonist Ac-[Arg⁶, Sar⁹, Met(O₂)¹¹] Substance P (6-11), ASMSP, in apulmonary tissue may be demonstrated as follows.

Male New Zealand white rabbits are euthanized via i.v. injection intothe ear vein with 60 mg/kg Nembutal (50 mg/mL). Preceding the Nembutalinto the vein is Heparin (1000 units/mL) at 0.0025 mL/kg foranticoagulant purposes. The chest cavity is opened from the top of therib cage to the sternum and the heart, lungs and part of the trachea areremoved. The pulmonary arteries are isolated from the rest of thetissues and cut in half to serve as pairs.

The segments are suspended between stainless steel stirrups, so as notto remove any of the endothelium, and placed in water-jacketed (37.0°C.) tissue baths containing physiological salt solution of the followingcomposition (mM): NaCl, 118.0; KCl, 4.7; CaCl₂, 1.8; MgCl₂, 0.54;NaH₂PO₄, 1.0; NaHCO₃, 25.0; glucose, 11.0; indomethacin, 0.005 (toinhibit cyclooxygenase); and dl-Propranolol, 0.001 (to block βreceptors); gassed continuously with 95% O₂-5% CO₂. Responses aremeasured on a Grass polygraph via Grass FT-03 transducers.

Initial tension placed on each tissue is 2 grams, which is maintainedthroughout the 1.0 hour equilibration period. Tissues are washed withthe physiological salt solution at 15 minute intervals. At the 30 and 45minute wash the following treatments are added: 1×10⁻⁶ M Thiorphan (toblock E.C.3.4.24.11), 3×1 0⁻⁸ M(S)-N-[2-(3,4-dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-N-methylbenzamide(to block NK₂ receptors), and the given concentration of the compoundbeing tested. At the end of the 1.0 h equilibration, 3×10⁻⁶ Mphenylephrine hydrochloride is added for 1.0 h. At the end of 1.0 h, adose relaxation curve to ASMSP is done. Each tissue is treated as aindividual and is considered finished when it fails to relax further for2 consecutive doses. When a tissue is complete, 1×10⁻³ M Papaverine isadded for maximum relaxation.

Percent inhibition is determined when a tested compound produces astatistically significant (p<0.05) reduction of the total relaxationwhich is calculated using the total relaxation of the Papaverine as100%. Potencies of the compounds are determined by calculating theapparent dissociation constants (K_(B)) for each concentration testedusing the standard equation:KB=[antagonist]/(dose ratio−1)where dose ratio=antilog[(agonist−log molar EC₅₀ without compound)−(−logmolar EC₅₀ with compound)]. The K_(B) values may be converted to thenegative logarithms and expressed as −log molar KB (i.e. pK_(B)). Forthis evaluation, complete concentration-response curves for agonistobtained in the absence and presence of the compound tested using pairedpulmonary artery rings. The potency of the agonist is determined at 50%of its own maximum relaxation in each curve. The EC₅₀ values areconverted to negative logarithms and expressed as −log molar EC₅₀.

NK₂ In Vitro Functional Assay (Test D)

The ability of a compound of the invention to antagonize the action ofthe agonist [β-ala8] NKA (4-10), BANK, in a pulmonary tissue may bedemonstrated as follows. Male New Zealand white rabbits are euthanizedvia i.v. injection into the ear vein with 60 mg/kg Nembutal (50 mg/mL).Preceding the Nembutal into the vein is Heparin (1000 units/mL) at0.0025 mL/kg for anticoagulant purposes. The chest cavity is opened fromthe top of the rib cage to the sternum and a small incision is made intothe heart so that the left and right pulmonary arteries can becannulated with polyethylene tubing (PE260 and PE1190 respectively). Thepulmonary arteries are isolated from the rest of the tissues, thenrubbed over an intimal surface to remove the endothelium, and cut inhalf to serve as pairs. The segments are suspended between stainlesssteel stirrups and placed in water-jacketed (37.0° C.) tissue bathscontaining physiological salt solution of the following composition(mM): NaCl, 118.0; KCl, 4.7; CaCl₂, 1.8; MgCl₂, 0.54; NaH₂PO₄, 1.0;NaHCO₃, 25.0; glucose, 11.0; and indomethacin, 0.005 (to inhibitcyclooxygenase); gassed continuously with 95% O₂-5% CO₂. Responses aremeasured on a Grass polygraph via Grass FT-03 transducers.

Initial tension placed on each tissue is 2 g, which is maintainedthroughout the 45 min equilibration period. Tissues are washed with thephysiological salt solution at 15 min intervals. After the 45 minequilibration period, 3×10⁻² M KCl is given for 60 min to test theviability of the tissues. The tissues are then washed extensively for 30min. The concentration of the compound being tested is then added for 30min. At the end of the 30 min, a cumulative dose response curve to BANKis performed. Each tissue is treated as a individual and is consideredfinished when it fails to contract further for 2 consecutive doses. Whena tissue is complete, 3×1 0⁻² M BaCl₂ is added for maximum contraction.

Percent inhibition is determined when a tested compound produces astatistically significant (p<0.05) reduction of the total contractionwhich is calculated using the total contraction of the BaCl₂ as 100%.Potencies of the compounds are determined by calculating the apparentdissociation constants (K_(B)) for each concentration tested using thestandard equation:K _(B)=[antagonist]/(dose ratio−1)where dose ratio=antilog[(agonist−log molar EC₅₀ without compound)−(−logmolar EC₅₀ with compound)]. The K_(B) values may be converted to thenegative logarithms and expressed as −log molar K_(B) (i.e. pK_(B)). Forthis evaluation, complete concentration-response curves for agonistobtained in the absence and presence of the compound tested using pairedpulmonary artery rings. The potency of the agonist is determined at 50%of its own maximum relaxation in each curve. The EC₅₀ values areconverted to negative logarithms and expressed as −log molar EC₅₀.NK₁ and NK₂ In Vivo Functional Assay (Test E)

The activity of a compound as an antagonist of NK₁ and/or NK₂ receptorsalso may be demonstrated in vivo in laboratory animals as described in:Buckner et al. “Differential Blockade by Tachykinin NK₁ and NK₂ ReceptorAntagonists of Bronchoconstriction Induced by Direct-Acting Agonists andthe Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotoninin the Anesthetized Guinea Pig.” J. Pharm. Exp. Ther., 1993, Vol 267(3),pp. 1168-1175. The assay is carried out as follows.

Compounds are tested in anesthetized guinea pigs pretreated with i.v.indomethacin (10 mg/kg, 20 min), propranolol (0.5 mg/kg, 15 min), andthiorphan (10 mg/kg, 10 min).

Antagonists or vehicle are administered i.v. and orally, 30 and 120 minprior to increasing concentrations of agonist, respectively. Theagonists used in these studies are ASMSP(Ac-[Arg⁶,Sar⁹,Met(O₂)¹¹]-SP(6-11)) and BANK (β-ala-8 NKA4-10).

Administered i.v., ASMSP is selective for NK₁ receptors, and BANK isselective for NK₂ receptors. Maximum response is defined as zeroconductance (G_(L), 1/R_(p)). ED₅₀ values are calculated (the dose ofagonist resulting in a reduction of G_(L) to 50% of baseline), andconverted to the negative logarithm (−logED₅₀). The ED₅₀ values,obtained in the presence (P) and absence (A) of antagonist, are used tocalculate a Dose Ratio (P/A), an expression of potency. Data areexpressed as mean±SEM and statistical differences were determined usingANOVA/Tukey-Kramer and Student's t-test, with p<0.05 consideredstatistically significant.

Compounds of the present invention exhibit marked activity in theforegoing tests and are considered useful for the treatment of thosediseases in which the NK₁ and/or NK₂ receptor is implicated, forexample, in the treatment of asthma and related conditions.

EXAMPLES

The invention will now be illustrated by the following non-limitingexamples, in which, unless stated otherwise:

-   -   (i) temperatures are given in degrees Celsius (° C.); unless        otherwise stated, operations were carried out at room or ambient        temperature, that is, at a temperature in the range of 18-25°        C.;    -   (ii) organic solutions were dried over anhydrous magnesium        sulfate or anhydrous sodium sulfate; evaporation of solvent was        carried out using a rotary evaporator under reduced pressure        (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up        to 60° C.;    -   (iii) chromatography means flash chromatography on silica gel;        thin layer chromatography (TLC) was carried out on silica gel        plates;    -   (iv) in general, the course of reactions was followed by TLC or        HPLC and reaction times are given for illustration only;    -   (v) melting points are uncorrected and (dec) indicates        decomposition;    -   (vi) final products had satisfactory proton nuclear magnetic        resonance (NMR) spectra;    -   (vii) when given, NMR data is in the form of delta values for        major diagnostic protons, given in parts per million (ppm)        relative to tetramethylsilane (TMS) as an internal standard,        determined at 300 MHz using deuterated chloroform (CDCl₃) as        solvent; conventional abbreviations for signal shape are used;        for AB spectra the directly observed shifts are reported;        coupling constants (J) are given in Hz; Ar designates an        aromatic proton when such an assignment is made;    -   (viii) reduced pressures are given as absolute pressures in        pascals (Pa); elevated pressures are given as gauge pressures in        bars;    -   (ix) non-aqueous reactions were run under a nitrogen atmosphere    -   (x) solvent ratios are given in volume:volume (v/v) terms; and    -   (xi) Mass spectra (MS) were run using an automated system with        atmospheric pressure chemical ionization (APCI). Generally, only        spectra where parent masses are observed are reported. The        lowest mass major ion is reported for molecules where isotope        splitting results in multiple mass spectral peaks (for example        when chlorine is present).

Terms and abbreviations: Solvent mixture compositions are given asvolume percentages or volume ratios. In cases were the NMR spectra arecomplex, only diagnostic signals are reported. DCM; methylene chloride,DMF; N,N-dimethylformamide, Et₂O; diethyl ether, EtOAc; ethyl acetate,HOAc; acetic acid, iPrOH; isopropanol, h; hour(s), min; minutes, NMR;nuclear magnetic resonance, MeOH; methanol, RT; room temperature, sat.;saturated, THF; tetrahydrofuran.

Methyl 3-cyano-2-methoxybenzoate. A stirred mixture of3-cyano-2-hydroxybenzoic acid (prepared as described in DE 2749518)(2.94 g, 18.1 mmol), dimethylsulfate (9.11 g, 72.2 mmol), potassiumcarbonate (9.98 g, 72.2 mmol) and acetone (40 mL) was heated at refluxfor 2.5 hr. The cooled mixture was filtered through a pad of Celite® andthe solvent removed from the filtrate in vacuo to yield a pale yellowsolid. The solid dissolved in EtOAc was washed with dilute HCl, sat.NaHCO₃ and brine; dried (Na₂SO₄), filtered and the solvent removed invacuo. Chromatography of the pale yellow solid through a 10 g Mega BondElut® column using DCM as eluent gave the title compound as a whitesolid; 3.28 g (95%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.04-8.06 (m, 1H),8.02-8.04 (m, 1H), 7.41 (t, 1H), 3.96 (s, 3H), 3.38 (s, 3H). MS APCI,m/z=192 (M+1).

3-Cyano-2-methoxybenzoic acid. A stirred solution of methyl3-cyano-2-methoxybenzoate (3.28 g, 17.2 mmol), lithium hydroxide hydrate(1.08 g, 25.8 mmol) in a mixture of THF (20 mL), water (8 mL) and MeOH(8 mL) was rapidly heated to a gentle reflux for 5 min and allowed tostir at ambient temperature for an additional 10 min. The mixture wasthen poured into water (30 mL) and sat. NaHCO₃ (5 mL) and extracted withEt₂O (50 mL). The aqueous phase was acidified to pH 2 with 1N HCl andthe resulting white precipitate was extracted with EtOAc (60 mL). TheEtOAc extract was washed with brine, dried (Na₂SO₄), filtered and thesolvent stripped in vacuo. The solid was twice treated with MeOH (15 mL)and toluene (30 mL) and the solvent stripped in vacuo to yield the titlecompound as a white solid; 2.89 g (95%). ¹H NMR (300 MHz, DMSO-d₆) δ13.48 (br.s, 1H), 7.98-8.03 (m, 2H), 7.38 (t, 1H), 3.96 (s, 3H).

N-[2-(S)-(3,4-Dichlorophenyl)-4-hydroxybutyl]-3-cyano-2-methoxybenzamide.A stirred suspension of 3-cyano-2-methoxybenzoic acid (2.9 g, 16.3 mmol)and oxalyl chloride (2.5 g, 19.5 mmol) in DCM (25 mL) was treated withDMF (10 μL) and bubbling was observed. The suspension became a clearsolution after 1 hr. After 90 min the solvent was evaporated to yield anoff-white solid. The solid was dissolved in 15 mL DCM, cooled to 0° C.and a suspension of 2-(S)-3,4-(dichlorophenyl)-4-hydroxybutanamine (S.C. Miller; WO 9410146) (4.2 g, 17.9 mmol) and 10 mL DCM was added in 1portion. 1N NaOH solution (25 mL) was then added and the solutionstirred rapidly for 30 min. The solution was acidified with 1N HCl andextracted with EtOAc. The EtOAc extract was washed with brine, dried(Na₂SO₄), filtered and the solvent removed in vacuo to yield a paleyellow viscous oil. Chromatography with DCM and 2%, 4%, 6% MeOH in DCMas eluent gave the title compound as a pale yellow oil-foam which wasdried under high vacuum; 6.5 g (quantitative). ¹H NMR (300 MHz, DMSO-d₆)δ 8.43 (t, 1H), 7.85 (dd, 1H), 7.53-7.59 (m, 3H), 7.25-7.31 (m, 2H),3.75 (s, 3H), 3.28-3.53 (m, 6H), 1.82-1.93 (m, 1H), 1.64-1.76 (m, 1H).MS APCI, m/z=393 (M+1).

N-[4-(tert-Butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-methoxybenzamide.To a stirred solution ofN-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-3-cyano-2-methoxybenzamide(6.5 g, 16.7 mmol) and tert-butyldimethylsilyl chloride (3.78 g, 25mmol) in DCM (30 mL) was added 4-(dimethylamino)pyridine (0.1 g, 0.8mmol) and triethylamine (2.7 g, 26.7 mmol). After 2 min a haze wasobserved above the solvent and 15 mL additional DCM was added to aidstirring. The solution was allowed to stir over a weekend. The reactionmixture was poured into a separatory funnel, diluted with water, DCM and50 mL sat. NaHCO₃ solution. The collected DCM layer was washed with 1MHOAc (50 mL), sat. NaHCO₃ solution (100 mL), dried (Na₂SO₄), filteredand the solvent removed in vacuo to yield a pale yellow clear oil.Chromatography with DCM as eluent yielded the title compound as a paleyellow oil, 8.2 g (97%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (t, 1H), 7.89(dd, 1H), 7.55-7.63 (m, 3H), 7.29-7.35 (m, 2H), 3.77 (s, 3H), 3.10-3.58(m, 7H), 0.87 (s, 9H), 0.00 (s, 3H), −0.02 (s, 3H). MS APCI, m/z=507(M+1).

N-[4-(tert-Butyldimethylsilanyloxy)-2-(S)(3,4-dichlorophenyl)butyl]-3-cyano-2-hydroxybenzamide.Magnesium iodide etherate was prepared from magnesium metal (1.02 g, 41mmol) and iodine (5.3 g, 21 mmol) in ether and added, via cannula, toN-[4-(tert-butyldimethylsilanyloxy)-2-(S)(3,4-dichlorophenyl)butyl]-3-cyano-2-methoxybenzamide(8.2 g, 16.2 mmol) dissolved in 20 mL dry benzene. Upon addition, thesolution turned progressively yellower. The mixture was heated at refluxfor 5 hr, cooled to RT and quenched with 50 mL ˜1M HOAc. DCM was addedand the mixture was transferred to a separatory funnel. The separatedDCM phase was dried (MgSO₄), filtered, and the solvent removed in vacuoto yield a very pale yellow solid. Chromatography with DCM and 2% MeOHin DCM as eluent gave the title compound as a white solid, 7.02 g (88%).¹H NMR (300 MHz, DMSO-d₆) δ 14.18 (s, 1H), 9.28 (t, 1H), 8.13 (dd, 1H),7.95 (d, 1H), 7.59-7.63 (m, 2H), 7.31 (dd, 1H), 7.11 (t, 1H), 3.20-3.65(m, 6H), 2.58 (br. s, 1H), 0.88 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). MSAPCI, m/z=493 (M+1).

N-[4-(tert-Butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-(3-hydroxy-2-(R)-methylpropoxy)benzamide.A stirred mixture of cesium carbonate (5.08 g, 15.6 mmol),N-[4-(tert-butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-hydroxybenzamide(5.90 g, 12.0 mmol) and 5 ml of dry DMF was heated at 65′ for 15 min and(R)-(−)-3-bromo-2-methyl-1-propanol (4.04 g, 26.4 mmol) was addeddropwise over 5 min. The oil bath was raised to 110° C. and the mixturestirred overnight. The cooled mixture was poured into 1 L of watercontaining 50 mL of sat NaCl and extracted with 250 mL and 200 mLportions of DCM. The combined extracts were washed with 500 mL of water,dried (Na₂SO₄), filtered and the solvent removed in vacuo. The residuewas chromatographed using 25%, 35% and 50% EtOAc/hexane as eluent toyield 2.90 g (49% recovered starting material) and 2.67 g (40%) of thetitle compound.

The above reaction repeated twice on sequentially recovered startingmaterial yielded 1.06 g (32%) and 0.61 g (31%) of additional titlecompound. Total yield was 4.34 g (64%) of white solid. ¹H NMR (300 MHz,CDCl₃) δ 8.23 (dd, 1H), 7.71 (dd, 1H), 7.59 (m, 1H), 7.41 (d, 1H),7.27-7.35 (m, 2H), 7.10 (dd, 1H), 4.02-4.14 (m, 2H), 3.39-3.88 (m, 6H),3.11-3.21 (m, 1H), 2.19-2.22 (m, 1H), 1.95-2.06 (m, 2H), 1.72-1.81 (m,1H), 0.94-1.05 (m, 3H), 0.87 (s, 9H), 0.00 (s, 6H)

N-[4-(tert-Butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-(3-methylsulfonyloxy-2-(R)-methylpropoxy)benzamide.To a stirred, cooled (ice-bath, 0°) solution ofN-[4-(tert-butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-(3-hydroxy-2-(R)-methylpropoxy)benzamide(4.64 g, 8.2 mmol) and triethylamine (1.74 mL, 12.5 mmol) in 72 mL ofDCM was added methanesulfonyl chloride (0.71 mL, 9.2 mmol) dropwise bysyringe. The mixture was stirred in the ice bath and allowed to warm toRT overnight. After 60 hr the reaction mixture was partitioned betweenwater and DCM, the layers separated and the organic layer washed twicewith portions of dilute HCl and sat. NaHCO₃, dried (Na₂SO₄), filteredand the solvent removed in vacuo. Chromatography with 8:2, 4:6, and 1:9hexane:Et₂O and 7:3 DCM:Et₂O as eluent returned the title compound as acolorless gum, 5.02 g (95%). MS APCI, m/z=643 (M+1).

5-[4-(tert-Butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine.A solution ofN-[4-(tert-butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-(3-methylsulfonyloxy-2-(R)-methylpropoxy)benzamide(5.02 g, 7.8 mmol) in DMF (100 mL) was added dropwise to a stirredslurry of 60% NaH (0.33 g, 8.2 mmol) in DMF (50 mL). The mixture wasplaced in an oil bath at 65° C. and stirred at that temperature for 1hr. The cooled reaction mixture was treated with DCM, water and sat.NH₄Cl, stirred 10 min and the layers separated. The organic phase waswashed twice with water, dried (Na₂SO₄), filtered and the solventremoved in vacuo. Chromatography with 8:2, 7:3 and 1:1 hexane:Et₂O aseluent returned 1.0 g (23%) of the title compound as a white solid. ¹HNMR (300 MHz, CDCl₃) δ 7.59 (bd, 1H), 7.39 (d, 1H), 7.29 (s, 2H), 7.12(d, 1H), 7.00 (t, 1H), 4.33-4.66 (m, 2H), 4.10 (dd, 1H), 3.13-3.63 (m,6H), 1.76-2.14 (m, 3H), 1.12 (br d, 3H), 0.89 (s, 9H), 0.01 (s, 3H),0.00 (s, 3H). MS APCI, m/z=547 (M+1).

Also obtained was 1.93 g (45%) ofN-[4-(tert-butyldimethylsilanyloxy)-2-(S)-(3,4-dichlorophenyl)butyl]-3-cyano-2-(2-methylallyloxy)benzamideas a colorless gum. ¹H NMR (300 MHz, CDCl₃) δ 8.33 (d, 1H), 7.12 (d,1H), 7.59 (br s, 1H), 7.30-7.42 (m, 3H), (7.07 9 d, 1H), 5.04 (br s,2H), 4.47 (s, 2H), 0.88 (s, 9H), 0.00-0.02 (m, 6H). MS APCI, m/z=547(M+1).

5-[4-Hydroxy-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine.A 1.0 M solution of tetrabutylammonium fluoride in THF (2.2 mL, 2.2mmol) was added to a stirred solution of5-[4-(tert-butyldimethylsilanyl-oxy)-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine(1.00 g, 1.83 mmol) and THF (20 mL) and the mixture stirred at ambienttemperature for 3.5 hr. The mixture was partitioned between DCM andwater, the organic layer collected, washed with water, dried (Na₂SO₄),filtered and the solvent removed in vacuo. The white solid was driedunder high vacuum overnight to yield 0.76 g (96%) of the title compound.¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, 1H), 7.26-7.40 (m, 3H), 6.98-7.12 (m,2H), 4.38 (br s, 2H), 4.07 (dd, 1H), 3.13-3.69 (m, 6H), 1.80-2.05 (m,3H), 1.61 (br s, 1H), 1.01-1.08 (m, 3H). MS APCI, m/z=433 (M+1).

5-[4-Methylsulfonyloxy-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine.To a stirred cooled (0° C., ice-bath) solution of5-[4-hydroxy-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine(0.35 g, 0.81 mmol) and triethylamine (0.184 mL, 1.32 mmol) in DCM (8mL) was added, dropwise from a pipette, methanesulfonyl chloride (0.076mL, 0.97 mmol) and the mixture allowed to stir in the bath and warm toRT. After 3 hr the reaction mixture was added to a 10 g Mega-Bond Elut®column, eluted with an additional 50 mL of DCM (discarded) and then 10%Et₂O in DCM. The first 100 mL of the 10% Et₂O in DCM eluent was strippedin vacuo to yield the title compound as a white foam (0.44 g,quantitative). ¹H NMR (300 MHz, CDCl₃) δ 7.59 (d, 1H), 7.42 (d, 1H),7.26-7.31 (m, 2H), 6.98-7.13 (m, 2H), 3.99-4.48 (m, 5H), 2.97 (s, 3H).MS APCI, m/z=511 (M+1).

5-[4-Azido-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine.To a stirred solution of5-[4-methylsulfonyloxy-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine(above crude, 0.81 mmol) in DMF (4 mL) was added sodium azide (0.137 g,2.04 mmol) and the mixture stirred at RT overnight. The mixture wasadded to water (100 mL) and extracted twice with DCM. The solvent wasstripped from the combined organic layer and the residue was dissolvedin EtOAc (40 mL), washed with brine (4×100 mL), dried (MgSO₄) filteredand the solvent removed in vacuo to yield the title compound as a solidfoam, 0.37 g (quantitative). ¹H NMR (300 MHz, CDCl₃) δ 7.59 (dd, 1H),7.41 (d, 1H), 7.30 (br s, 2H), 6.98-7.11 (m, 2H), 4.38 (br s, 2H), 4.11(m, 1H), 3.05-3.34 (m, 5H), 1.81-2.09 (m, 3H), 1.11 (br s, 2H). MS APCI,m/z=458 (M+1).

5-[4-Amino-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine. The following is a modification of the method of Rao andSiva, Synth. Commun. 24(4) 549 (1994). To a stirred cooled (ice-bath)mixture of5-[4-azido-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine(the above crude, 0.81 mmol), copper(II) sulfate (0.026 g, 0.10 mmol)and MeOH (2 mL) was added sodium borohydride (0.31 g, 8.2 mmol) in oneportion and the mixture stirred at RT overnight. Some starting mesylateremained as shown by TLC (silica gel, 2% MeOH/DCM) so that the mixturewas re-cooled in an ice-bath and additional NaBH₄ (0.175 g, 4.6 mmol)added. After stirring 2 hr in the ice-bath and 3 hr at ambienttemperature 1N NaOH was added to achieve pH 12 and the mixturepartitioned between water and DCM. The organic layer was collected,washed twice with water, dried (Na₂SO₄), filtered and the solventstripped in vacuo. Chromatography using 5%, 10% and 20% MeOH/DCM aseluent returned the title compound as a white solid (0.24 g, 69%);converted to the citrate salt, mp 82-128° C. Calcd forC₂₂H₂₃Cl₂N₃O₂.C₆H₈O₇.H₂O: C, 52.34; H, 5.18; N, 6.54. Found: C, 52.21;H, 5.13; N, 6.26. ¹H NMR (300 MHz, CDCl₃) δ 7.58 (d, 1H), 7.38 (d, 1H),7.26-7.33 (m, 2H), 7.06-7.15 (br m, 1H) 7.00 (t, 1H), 4.26-4.55 (br m,2H), 4.07 (dd, 1H). MS APCI, m/z=432 (M+1).

5-[3-Carboxy-2-(S)-(3,4-dichlorophenyl)propyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine.To a cooled (ice-bath, 0° C.) stirred mixture of Jones Reagent [0.60 mLof a solution prepared from CrO₃ (2.73 g, 27.3 mmol), H₂SO₄ (2.3 mL) andwater (10.0 mL)] and acetone (10 mL) was added dropwise a solution of5-[4-hydroxy-2-(S)-(3,4-dichlorophenyl)butyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine(0.329 g, 0.76 mmol) and 14 mL of acetone. After stirring 2 hr at RT thereaction was quenched by the dropwise addition of i-PrOH until a bluecolor persisted (˜3 mL). After 15 min the reaction mixture waspartitioned between DCM and water, the organics separated, washed withwater, dried (Na₂SO₄), filtered and the solvent stripped in vacuo.Chromatography using 5%, 10% and 20% MeOH/DCM as eluent returned thetitle compound as a white solid (0.326 g, 96%). ¹H NMR (300 MHz,DMSO-d₆) δ 12.10 (s, 1H), 7.80 (dd, 1H), 7.50-7.56 (m, 2H), 7.28 (dd,1H), 7.17 (br s, 1H), 7.10 (t, 1H). MS APCI, m/z=447 (M+1), 445 (M−1).

5-[3-Aminocarbonyl-2-(S)-(3,4-dichlorophenyl)propyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine.To a stirred solution of5-[3-carboxy-2-(S)-(3,4-dichlorophenyl)propyl]-10-cyano-3-(R)-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine(0.326 g, 0.73 mmol) and DMF (8 mL) was added HOBt.NH₃ (0.273 g, 1.80mmol) and 1-[3-(dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride(0.287 g, 1.50 mmol) and the mixture stirred at RT overnight. Thereaction mixture was treated with sat NaHCO₃, DCM and a large volume ofwater. The organics were collected, washed twice with a large volume ofwater, dried (Na₂SO₄), filtered and the solvent stripped in vacuo.Chromatography using 0.5%, 1%, 2% and 5% MeOH/DCM as eluent returned0.240 g (78%) of the title compound as a white solid, mp 92-144°. Calc'dfor C₂₂H₂₁Cl₂N₃O₃.H₂O: C, 60.70; H, 4.89; N, 8.16. Found: C, 60.73, H,4.71; N, 7.53. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (s, 1H), 7.74 (dd, 1H),7.42-7.47 (m, 3H), 7.24-7.27 (m, 1H), 6.71-6.74 (m, 1H), 5.56 (br s,1H), 5.32 (br s, 1H), 4.80 (t, 1H), 4.65 (dd, 1H), 3.80 (q, 1H),3.57-3.67 (m, 1H), 3.23-3.30 (m, 3H), 2.55-2.71 (m, 2H), 2.29-2.39 (m,1H), 1.21 (t, 1H), 0.98 (d, 3H). MS APCI, m/z=446 (M+1).

1. A method of treating major depressive disorder or emesis comprisingadministering a therapeutically-effective amount of a compound havingthe formula

wherein: R^(1a) is H, NR⁹R¹⁰, —OR⁹,

R^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) and R^(1c)together are ═O, ═CH₂ or —OCH₂CH₂O—; R² is H, oxo, —OR⁹ or —CH₃; R³, R⁴,R⁵ and R⁶ are each independently selected from H, cyano, nitro,trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl, and C₁₋₆alkyl substituted bycyano, nitro, trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl,halo, —OR⁹, —OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —NR⁹C(═O)R¹⁰, or aminosulfonyl; wherein atleast one of R³, R⁴, R⁵ and R⁶ is H; R⁹ and R¹⁰ are each independently Hor C₁₋₆alkyl; R¹¹ is phenyl, substituted in at least the ortho positionby C₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,trifluoromethylthio, trifluoromethylsulfinyl, C₁₋₆alkanesulfonamido,C₁₋₆alkanoyl, C₁₋₆alkoxy-carbonyl, succinamido, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,C₁₋₆alkoxy-C₁₋₆alkylcarbamoyl, N-methylcarbamoyl, C₁₋₆alkanoylamino,ureido, C₁₋₆ureido, di-C₁₋₆alkylureido, amino, C₁₋₆alkylamino, ordi-C₁₋₆alkylamino; R¹² is selected from hydrogen, hydroxy, C₁₋₆alkoxy,C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino,C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl and bis(C₁₋₆alkyl)carbamoyl;R¹³ is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—; R¹⁴ is hydrogen,hydroxy, C₁₋₆alkoxy, C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkanoylamino, C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl or di-C₁₋₆alkylcarbamoyl; M is —C(═O)— or —S(═O)₂—; L is —NH— or —CH₂—; X¹ and X²are independently H or halogen, wherein at least one of X¹ and X² ishalogen; Y and Z are CH₂ or O, wherein Y does not equal Z; and n is 0 or1; or any pharmaceutically-acceptable salt thereof, or any compositioncomprising the same.
 2. A method according to claim 1 wherein R³, R⁴, R⁵and R⁶ are selected from H, cyano, nitro, —S(═O)C₁₋₆alkyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and —C₁₋₆alkylcyano; wherein atleast two of R³, R⁴, R⁵ and R⁶ are H.
 3. A method according to claim 1wherein R³, R⁴, R⁵ and R⁶ are selected from H, cyano, methoxy, ethoxy,isopropoxy, fluoro, bromo, chloro, iodo, nitro, cyanomethyl, carboxy,carbamoyl, ethynyl, methyl, ethyl, dimethylcarbamoyl, methylsulfonyl,aminosulfonyl, prop-2-enyl, acetyl and acetylamino; wherein at least twoof R³, R⁴, R⁵ and R⁶ are H.
 4. A method according to claim 1 wherein R³,R⁴, R⁵ and R⁶ are selected from H, cyano, methoxy, ethyl, fluoro andnitro; wherein at least two of R³, R⁴, R⁵ and R⁶ are H.
 5. A methodaccording to claim 1 wherein: R^(1a) is

R^(1b) is H; and R^(1c) is H.
 6. A method according to claim 1 wherein:R^(1a) is

R^(1b) is H; and R^(1c) is H.
 7. A method according to claim 1 whereinR^(1a) is H, NR⁹R¹⁰ or —OR⁹.
 8. A method according to claim 1 wherein R²is —OR⁵ or —CH₃.
 9. A method of treating severe anxiety disorders,stress disorders, major depressive disorder with anxiety, eatingdisorders, bipolar disorders, substance abuse disorder, schizophrenicdisorders, psychotic disorders, movement disorders, cognitive disorders,depression, anxiety, mania or hypomania, aggressive behaviour, obesity,rheumatoid arthritis, Alzheimer's disease, cancer, oedema, allergicrhinitis, inflammation, pain, gastrointestinal-hypermotility,Huntington's disease, COPD, hypertension, migraine, bladderhypermotility, or urticaria comprising administering atherapeutically-effective amount of a compound having the formula

wherein: R^(1a) is H, NR⁹R¹⁰, —OR⁹,

R^(1b) and R^(1c) are independently H or —OR⁹, or R^(1b) and R^(1c)together are ═O, ═CH₂ or —OCH₂CH₂O—; R² is H, oxo, —OR⁹ or —CH₃; R³, R⁴,R⁵ and R⁶ are each independently selected from H, cyano, nitro,trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl, halo, —OR⁹,—OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl, and C₁₋₆alkyl substituted bycyano, nitro, trifluoromethoxy, trifluoromethyl, C₁₋₆alkylsulfonyl,halo, —OR⁹, —OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —NR⁹C(═O)R¹⁰, or aminosulfonyl; wherein atleast one of R³, R⁴,R⁵ and R⁶ is H; R⁹ and R¹⁰ are each independently Hor C₁₋₆alkyl; R¹¹ is phenyl, substituted in at least the ortho positionby C₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,trifluoromethylthio, trifluoromethylsulfinyl, C₁₋₆alkanesulfonamido,C₁₋₆alkanoyl, C₁₋₆alkoxy-carbonyl, succinamido, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,C₁₋₆alkoxy-C₁₋₆alkylcarbamoyl, N-methylcarbamoyl, C₁₋₆alkanoylamino,ureido, C₁₋₆ureido, di-C₁₋₆alkylureido, amino, C₁₋₆alkylamino, ordi-C₁₋₆alkylamino; R¹² is selected from hydrogen, hydroxy, C₁₋₆alkoxy,C₁₋₆alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoylamino,C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl and bis(C₁₋₆alkyl)carbamoyl;R¹³ is —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—; R¹⁴ is hydrogen,hydroxy, C₁₋₆alkoxy, C¹⁻⁶alkanoyloxy, C₁₋₆alkanoyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkanoylamino, C₁₋₆alkyl, carbamoyl, C₁₋₆alkylcarbamoyl or di-C₁₋₆alkylcarbamoyl; M is —C(═O)— or —S(═O)₂—; L is —NH— or —CH₂—; X¹ and X²are independently H or halogen, wherein at least one of X¹ and X² ishalogen; Y and Z are CH₂ or O, wherein Y does not equal Z; and n is 0 or1; or any pharmaceutically-acceptable salt thereof, or any compositioncomprising the same.
 10. A method according to claim 9 wherein R³, R⁴,R⁵ and R⁶ are selected from H, cyano, nitro, —S(═O)C₁₋₆alkyl, halo,—OR⁹, —OCH₂O—, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —NR⁹C(═O)R¹⁰, aminosulfonyl and—C₁₋₆alkylcyano; wherein at least two of R³, R⁴, R⁵ and R⁶ are H.
 11. Amethod according to claim 9 wherein R³, R⁴, R⁵ and R⁶ are selected fromH, cyano, methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo,nitro, cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl,dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyland acetylamino; wherein at least two of R³, R⁴, R⁵ and R⁶ are H.
 12. Amethod according to claim 9 wherein R³, R⁴, R⁵ and R⁶ are selected fromH, cyano, methoxy, ethyl, fluoro and nitro; wherein at least two of R³,R⁴, R⁵ and R⁶ are H.
 13. A method according to claim 9 wherein: R^(1a)is

R^(1b) is H; and R^(1c) is H.
 14. A method according to claim 9 wherein:R^(1a) is

R^(1b) is H; and R^(1c) is H.
 15. A method according to claim 9 whereinR^(1a) is H, NR⁹R¹⁰ or —OR⁹.
 16. A method according to claim 9 whereinR² is —OR⁵ or —CH₃.